Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders.This capacity is not innate but is activated or‘licensed’by inflammatory cytoki...Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders.This capacity is not innate but is activated or‘licensed’by inflammatory cytokines.The licensing mechanism remains unclear.Here,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity.In response to stimulation by inflammatory cytokines,MSCs exhibited a dramatic increase in the consumption of glucose,which was accompanied by an enhanced use of nicotinamide adenine dinucleotide(NAD^(+))and increased expression of nicotinamide phosphoribosyltransferase(NAMPT),a central enzyme in the salvage pathway for NAD^(+) production.When NAD^(+) synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated.Consequently,when NAD^(+) metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury.Further analysis revealed that NAMPT-driven production of NAD^(+) was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs.Furthermore,the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle,which led to hypoxia-inducible factor 1α(HIF-1α)stabilization and subsequently increased the transcription of key glycolytic genes,thereby persistently maintaining glycolytic flux.This study demonstrated that unlike its proinflammatory role in immune cells,NAD^(+) metabolism governs the anti-inflammatory function of MSCs during inflammation.展开更多
Mesenchymal stromal/stem cells(MSCs)possess multi-lineage differentiation and self-renewal potentials.MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases,due to the potent...Mesenchymal stromal/stem cells(MSCs)possess multi-lineage differentiation and self-renewal potentials.MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases,due to the potent immunoregulatory functions of MSCs.An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions.Growth factors,cytokines,chemokines,extracellular matrix components,and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms.These secretory factors contribute to immune modulation,tissue remodeling,and cellular homeostasis during regeneration.In this review,we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.展开更多
基金supported by grants from the National Key R&D Program of China(2021YFA1100600 and 2022YFA0807300)the National Natural Science Foundation of China(82202032,81930085 and 32150710523)the Jiangsu Province International Joint Laboratory for Regenerative Medicine Fund and the Suzhou Foreign Academician Workstation Fund(SWY202202).
文摘Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders.This capacity is not innate but is activated or‘licensed’by inflammatory cytokines.The licensing mechanism remains unclear.Here,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity.In response to stimulation by inflammatory cytokines,MSCs exhibited a dramatic increase in the consumption of glucose,which was accompanied by an enhanced use of nicotinamide adenine dinucleotide(NAD^(+))and increased expression of nicotinamide phosphoribosyltransferase(NAMPT),a central enzyme in the salvage pathway for NAD^(+) production.When NAD^(+) synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated.Consequently,when NAD^(+) metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury.Further analysis revealed that NAMPT-driven production of NAD^(+) was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs.Furthermore,the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle,which led to hypoxia-inducible factor 1α(HIF-1α)stabilization and subsequently increased the transcription of key glycolytic genes,thereby persistently maintaining glycolytic flux.This study demonstrated that unlike its proinflammatory role in immune cells,NAD^(+) metabolism governs the anti-inflammatory function of MSCs during inflammation.
基金grants from the National Key R&D Program of China(2018YFA0107500,2021YFA1100600)National Natural Science Foundation of China(81930085,32150710523 and 31961133024)+3 种基金Jiangsu Province International Science and Technology Cooperation Program(BZ2019017)National Center for International Research-Cambridge-Su Genomic Research Center(2017B01012)the State Key Laboratory of Radiation Medicine and Protection,Soochow University(GZN1201804 and GZN1201903)Ministry of Health(IDI-IRCCS)&MAECI Italy-China Science and Technology Cooperation(#PGR00961)to E.C.
文摘Mesenchymal stromal/stem cells(MSCs)possess multi-lineage differentiation and self-renewal potentials.MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases,due to the potent immunoregulatory functions of MSCs.An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions.Growth factors,cytokines,chemokines,extracellular matrix components,and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms.These secretory factors contribute to immune modulation,tissue remodeling,and cellular homeostasis during regeneration.In this review,we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
